Successful treatment of metastasis continues to be the main challenge in cancer. Local chest wall recurrences of breast cancer often occur in the context of metastatic disease, presenting the challenge of treating both. In this setting, salvage chemotherapy/hormone therapy result in overall response rates of only 20-30%, warranting novel treatment strategies. Our group has demonstrated that local ionizing radiation therapy (RT) can be successfully combined with immunotherapy (IT) strategies to generate an anti-tumor immune response, enabling not only rejection of the treated tumor, but also of metastases outside the irradiated field (abscopal effects). Imiquimod (IMQ) is a small molecule immune response modifier which triggers immune activation via toll-like receptor (TLR)-7 and is FDA approved, based on its clinical activity against a variety of skin cancers. In preclinical models of breast cancer, the syngeneic murine tumors TSA and 4T1, we have shown that the combination of local RT with topical IMQ successfully delayed both primary tumor growth and metastases. We propose a clinical trial that translates the preclinical experience of combining topical imiquimod and local radiotherapy to the setting of metastatic breast cancer patients who also have chest wall recurrences. The strategy is that of vaccinating patients against their own tumor to generate an immune response that, if successful, can be detected outside the field of local therapies. The specific aims are to: 1. Determine the safety and therapeutic efficacy of topical IMQ and concurrent local RT in breast cancer patients with cutaneous metastases. 2. Determine the effects of TLR7 agonist IMQ and RT on tumor-specific T cell immunity and tumor immune signature. The selection of breast cancer patients with chest wall recurrences is based on the following rationale: 1) the accessibility of the lesions to topical agent (imiquimod) and to radiotherapy; 2) the ease to visually monitor local response and to perform Fine Needle Aspiration biopsies for mechanistic studies. A Phase I/II trial will be conducted to evaluate the safety of the combination of RT and IMQ, topically applied to skin metastases of breast cancer. Efficacy is measured with respect to local tumor regression as well as systemic responses (outside the field of combined therapy), as a demonstration of an effective anti-tumor immune response. Immunomonitoring will consist of an analysis of tumor-specific T cell immunity and an assessment of immune signatures in the tumor, to learn whether the proposed treatment induces tumor- specific T cell responses and generates a tumor immune signature consistent with immunological rejection. The proposed studies will create the basis for a potential paradigm shift with direct clinical implications: harnessing a novel combination to effectively immunize the patient to her own tumor, and thereby achieving a response of the systemic disease.